Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

 

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The paragraph you provided describes a study where researchers aimed to target the peptidyl-prolyl isomerase called Pin1, which plays a role in activating oncogenes and inactivating tumor suppressors in cancer. Despite previous difficulties in targeting Pin1, the researchers screened a library of electrophilic fragments to find covalent inhibitors that can bind to Pin1's active site Cys113. Through this process, they developed a specific and potent Pin1 inhibitor called Sulfopin.

Sulfopin was shown to selectively inhibit Pin1 through two different chemoproteomics methods, demonstrating its specificity. It effectively engaged the target Pin1 in cellular and in vivo settings and mimicked the effects observed in Pin1 genetic knockout experiments. However, inhibiting Pin1 had only a moderate impact on the viability of cancer cell lines.

Nevertheless, Sulfopin treatment led to the downregulation of c-Myc target genes, reduced tumor progression, and provided a survival advantage in animal models of MYCN-driven neuroblastoma and pancreatic cancer. These findings suggest that Sulfopin, as a chemical probe, can be used to study Pin1-dependent pharmacology in cells and in living organisms. Furthermore, the study suggests that Pin1 is a promising candidate for further investigation as a potential target for cancer therapy.

In summary, the researchers identified Sulfopin as a potent and selective Pin1 inhibitor, which showed promising effects in preclinical models of neuroblastoma and pancreatic cancer. The study suggests that Pin1 inhibition could be a viable strategy for cancer treatment and warrants further research.

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S9782	Sulfopin	Sulfopin (PIN1-3) is a highly selective covalent inhibitor of Pin1 with a Ki of 17 nM in the FP assay. Sulfopin blocks Myc-driven tumor initiation and growth in vivo.

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